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European Journal of Heart Failure 2001 3(1):21-26; doi:10.1016/S1388-9842(00)00090-8
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© 2001 European Society of Cardiology

Plasma and pericardial fluid natriuretic peptide levels in postinfarction ventricular dysfunction

Rauli Klemolac, Ilkka Tikkanena,b, Olli Vuolteenahoc, Lauri Toivonenb and Mika Lainea,b,*

a Department of Medicine, Helsinki University Central Hospital Haartmaninkatu, FIN-00250, Helsinki, Finland
b Minerva Foundation Institute for Medical Research Tukholmankatu 2, FIN-00250, Helsinki, Finland
c Department of Physiology, University of Oulu Kajaanintie 52A, FIN-90220, Oulu, Finland

* Corresponding author. Fax: +358-9-477-00425. E-mail address: mklaine{at}saunalahti.fi (M. Laine).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims: In the present study we examined plasma and pericardial fluid ANP and BNP concentrations in postinfarction ventricular dysfunction. The association of peptide levels to left ventricular (LV) dysfunction and to the localization of the myocardial infarction (MI) was studied.

Methods and results: Plasma and pericardial fluid samples were obtained from 37 patients undergoing coronary bypass surgery. According to the ECG and preceding coronary angiography, the patients were divided into three groups: previous anterior myocardial infarction (MI) (n = 12), previous inferior/posterior MI (n = 15) and no history of MI (n = 10). When compared to the control group with no MI, the patients with anterior MI had elevated plasma ANP and BNP (134 ± 13 vs. 81 ± 15 pg/ml, P < 0.01 and 95 ± 10 pg/ml vs. 26 ± 8 pg/ml, P < 0.01, respectively) and pericardial fluid BNP (473 ± 60 pg/ml vs. 57 ± 8 pg/ml, P < 0.001) levels. The plasma natriuretic peptide concentrations were not increased in the patients with inferior/posterior MI, but the pericardial fluid BNP concentrations were greater than in the patients with no history of MI (129 ± 35 pg/ml vs. 57 ± 8 pg/ml, P < 0.05). Six of the 12 patients with previous anterior MI had LVEF ≥ 45%. Despite their normal LV systolic function, these patients had increased plasma and pericardial fluid BNP levels when compared to the group with no history of MI (68 ± 18 pg/ml vs. 26 ± 8 pg/ml, P < 0.05 and 534 ± 258 pg/ml vs. 57 ± 8 pg/ml, P < 0.01, respectively).

Conclusions: Previous anterior myocardial infarction was associated with increased cardiac BNP production even if the LV systolic function was normal (LVEF ≥ 45%). The high pericardial fluid BNP concentrations in postinfarction patients suggest that the BNP synthesis and release are augmented in the ventricular myocardium independent from the LVEF.

Key Words: Natriuretic peptides • Myocardial infarction • Heart failure • ANF • Remodelling • Hypertrophy

Received February 20, 2000; Revised May 15, 2000; Accepted May 23, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Transmural myocardial infarction results in neurohormonal activation, as a compensation for the impaired contraction force of the myocardium [1]. In acute myocardial infarction (MI) the plasma levels of circulating natriuretic peptides (ANP, BNP and their N-terminal propeptides N-ANP and N-BNP) correlate with cardiac dysfunction as measured by left ventricular ejection fraction (LVEF) [2,3]. The higher release of natriuretic peptides in the acute phase is considered to be associated with increased filling pressures [4] resulting in mechanical load, which is the principal stimulus for the synthesis and release of ANP and BNP [5]. Although in acute infarction, natriuretic peptides mainly originate from the atria, the failing ventricular myocardium starts gradually to synthesize and secrete increasing amounts of ANP and BNP [6]. This is a component of the altered gene expression in the myocardial remodeling that occurs after MI.

Large mortality trials have shown that a low LVEF after MI is associated with increased mortality and it is well demonstrated in a number of studies, that ACE-inhibitors decrease mortality in this subgroup [7]. In clinical practice, ACE-inhibitors are routinely used for those with an ejection fraction less than 40%. Elevated plasma levels of ANP, N-ANP and BNP are associated with decreased left ventricular function and decreased long-term survival after acute MI [8–10]. An intriguing finding is that elevated plasma BNP levels seem to provide prognostic information independent from the left ventricular systolic function [11]. This suggests that the post-MI patients with normal or only slightly decreased ventricular function but elevated plasma BNP levels are a higher risk group.

A sustained elevation of plasma BNP levels has previously been associated with progressive ventricular remodeling after acute myocardial infarction [12]. The magnitude of the myocardial remodeling and hypertrophy after MI is dependent on the size of the initial damage to the left ventricle. Large anterior q-wave infarction is associated with higher long-term mortality than the usually less damaging inferior/posterior q-wave infarction.

The aim of this study was to investigate ANP and BNP levels in plasma and pericardial fluid in a cross-sectional sample of post-MI patients. The hormone concentrations were correlated to the findings on coronary angiography and to left ventricular systolic function. The hypothesis was that previous anterior myocardial infarction is associated with increased natriuretic peptide release independent of the LV ejection fraction. The patients were divided into three groups according to the localization of the MI: (1) the patients with initial damage to the left ventricle due to anterior infarction; (2) the patients who had previously had an inferior or posterior infarction; and (3) a control group with no history of MI. The analysis of the pericardial fluid was used to study the local paracrine release of natriuretic peptides from the myocardium.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
Informed consent was obtained from all patients for participation in the study according to a protocol approved by the ethics committee of the University of Helsinki. The investigation conforms with the principles outlined in the Declaration of Helsinki. We studied 37 consecutive patients (26 men, 11 women) who underwent coronary bypass operation. The age of the patients ranged from 44 to 76, with a mean age of 61 years. Patients with acute MI, haemodynamically significant valvular disease, atrial fibrillation or congenital heart disease were excluded from the study. The clinical record of each patient was reviewed for determinations of their New York Heart Association (NYHA) class. Seven of the patients were classified to NYHA class IV, 20 of the patients to NYHA class III and 10 of the patients to NYHA class II. Ongoing drug treatments included beta-blockers, angiotensin converting enzyme inhibitors (ACE), nitrates, calcium channel blockers, digitalis and diuretics. All drugs were withheld on the day of the study.

2.2. Cardiac catheterization
Coronary angiography and left ventriculography and 12-lead electrocardiogram (ECG) were performed in each patient. Left ventricular ejection fraction (LVEF) was determined by left ventriculography. According to the ECG and to the findings on cardiac catheterization, patients were divided in the three groups: (i) previous anterior MI (n=12), if they had a total occlusion in LAD or q-waves in at least two anterior EKG leads; (ii) previous inferior/posterior MI, if they had a total occlusion in RCA/LCx or q-waves in inferior/posterior EKG leads (n=14); and (iii) no coronary artery occlusions and/or no documented history of transmural MI (n=10). LV dysfunction was defined as LVEF<45%. Catheterization data were interpreted blindly with respect to the natriuretic peptide levels.

2.3. Measurement of ANP and BNP
Venous blood samples were withdrawn on the morning before the coronary by-pass operation. After 30 min of rest, 10 ml of venous blood was drawn from a venous cannula in the forearm. The pericardial fluid samples were taken immediately after opening the pericardium during coronary by-pass operation. Samples for the assay of plasma and pericardial fluid ANP and BNP concentrations were transferred to chilled disposable tubes containing EDTA (1 mg/ml). The samples were immediately placed on ice and centrifuged at 4°C for 10 min. Plasma and pericardial fluid ANP and BNP concentrations were measured with radioimmunoassay as described earlier [13]. The ANP assay has <0.1% cross-reaction with NT-proANP, BNP or CNP. The BNP assay has <0.1% cross-reaction with NT-proBNP, BNP or CNP. Both assays cross-react 100% with their respective prohormones (proANP and proBNP). The sensitivity of both assays was 1 fmol/tube and the intra-and interassay coefficients of variation <10 and <15%, respectively.

2.4. Statistical analysis
The results are expressed as mean±S.E.M. Linear regression analysis was used to analyze the relationship between LVEF and hormone levels. Comparisons between groups with (LVEF<45%) and without (LVEF≥45%) LV dysfunction were assessed by t-tests. When comparison of multiple groups was needed, we used one-way and/or two-way analysis of variance. Results were considered statistically significant at the level of P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The mean LVEF (±S.E.M.) was 60±6% in the control group (n=10) with no previous infarction (Fig. 1). Within those patients who had a history of inferior/posterior MI (n=15), the mean LVEF, 52±9%, was slightly lower, but the difference was not statistically significant. The patients with history of anterior MI (n=12) had significantly lower mean LVEF, 44±11%, P<0.01, than the control group. Among the 27 patients with a previous MI, there were 12 patients with an ejection fraction less than 45% and 15 patients ≥45%.


Figure 1
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  		Fig. 1 Left ventricular ejection fraction of the patients with no previous myocardial infarction (MI), inferior/posterior MI or anterior MI. The open symbols represent individual patients and the filled symbols are means±S.E.M.

 
The plasma ANP (134±13 pg/ml) and BNP (95±10 pg/ml) levels in the group with a history of anterior MI were significantly higher (P<0.05 and P<0.01, respectively), when compared to the control group with no history of MI (81±15 pg/ml and 26±8 pg/ml) (Fig. 2). There were no statistically significant differences in the plasma ANP or BNP levels between the patients with previous inferior/posterior infarction and the control group (P=NS).


Figure 2
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  		Fig. 2 Plasma and pericardial fluid ANP and BNP levels (mean±S.E.M.) in the patients with no previous myocardial infarction (MI), inferior/posterior MI or anterior MI.

 
Next we tested whether this increase in ANP and BNP plasma levels after anterior MI is due to the impaired LVEF (Table 1). Six of the 12 patients with anterior MI had LVEF ≥45%. Despite the normal LV function, the mean plasma BNP level (68±18 pg/ml) in this subgroup was higher than in the control group (26±8 pg/ml, P<0.05). In contrast, there was no statistically significant differences in the ANP plasma levels between the control group and patients with previous anterior MI but normal LVEF. This suggests that the plasma ANP level is more directly related to left ventricular systolic function than BNP. Indeed, two-way analysis of variance showed that the history of anterior MI was associated with the high plasma BNP levels independently of LVEF, whereas the plasma ANP levels had an interaction with LV function (P<0.01).


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  		Table 1
 
Pericardial fluid analyses were used to study the cardiac paracrine release of ANP and BNP in post-MI patients. Pericardial fluid is generated as an ultrafiltrate through the ventricular myocardium and reflects the hormone concentrations in the myocardial interstitial fluid. The mean pericardial fluid ANP level was 2.5-fold and BNP level 4.2-fold higher when compared to the plasma concentrations. The pericardial fluid BNP concentration was increased in the post-MI patients. Pericardial fluid BNP levels were significantly higher in the group with history of inferior/posterior MI (129±35 pg/ml, P<0.05) and in the group with history of anterior MI (473±60 pg/ml, P<0.001), when compared to the patients with no history of MI (57±8 pg/ml). There were no statistically significant differences in the pericardial fluid ANP levels between the three groups (P=NS), although, there was a trend favouring higher ANP levels in the patients who had a history of MI.

Linear regression analysis did not show a correlation between LVEF and pericardial fluid ANP or BNP levels (Fig. 3). This was due to the fact that some post-MI AMI patients (Fig. 3, open symbols) had high pericardial fluid natriuretic peptides while the LVEF was normal or only modestly impaired. When we compared pericardial fluid ANP and BNP levels in the patients with LVEF ≥45% and <45% there were no statistically significant differences between the two groups (Table 1). In two-way analysis of variance, the patients with previous anterior MI had elevated pericardial fluid BNP levels independent of LVEF.


Figure 3
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  		Fig. 3 Correlation of the pericardial fluid ANP and BNP levels to the left ventricular ejection fraction. Open symbols represent the post MI patients and closed symbols are the control patients with no history of MI. Horizontal lines show 95% confidence intervals for the control values.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The present study shows elevated plasma and pericardial fluid BNP levels in postinfarction patients when compared to patients with no history of MI. The highest BNP levels were detected in the patients with previous anterior MI independent of LV systolic function.

It is has been well established in many studies that the plasma levels of circulating natriuretic peptides are increased in heart failure [14–17]. Because the clinical diagnosis of heart failure is difficult, natriuretic peptides (or their N-terminal propeptides) have been suggested as non-invasive markers for heart failure. Especially important would be the detection of asymptomatic LV dysfunction [14,18].

One of the most common reasons for the development of chronic LV systolic dysfunction is myocardial infarction. In acute MI both ANP and BNP plasma levels increase rapidly [13]. The peak ANP levels occur at the time of admission, whereas BNP plasma levels increase until up to 1–2 days. This difference is probable due to the different secretion mechanism of ANP and BNP. ANP is stored in secretory granules (mainly in the atria) and released rapidly in response to a pressure stimulus, whereas BNP secretion is regulated more at the level of gene expression and BNP is released both by the atrial and ventricular myocardium [5].

In acute myocardial infarction, LV systolic function is usually assessed by echocardiography. ACE-inhibitors are routinely used for those with markedly impaired LVEF. However, most postinfarction patients are followed outside the hospital and it has been suggested that plasma circulating natriuretic peptides could be used as non-invasive markers of LV dysfunction.

In our study, increased plasma ANP and BNP concentrations were found in the patients who had a history of anterior MI. Plasma BNP levels were normal among the patients with history of damage due to inferior/posterior infarction. Our results support those obtained by Sigurdson et al. [1] who followed the plasma concentrations of neurohormones longitudinally for up to 6 months in patients with acute myocardial infarction. They found that early neurohormonal activation occurred in almost all patients, whereas prolonged or sustained activation occurred only in the patients with extensive myocardial damage or in the patients with clinical signs of heart failure.

It can be argued that anterior MI results in decreased LV systolic function and thereby in elevated circulating natriuretic peptide levels. This was the case in our study with plasma ANP levels, but does not seem hold entirely true with plasma BNP levels. In the present study BNP levels were also increased in the post-MI patients with normal LVEF. After the infarction, myocardial hypertrophy may partly compensate for the initial decrease in LV systolic function. It has been established in many studies that in myocardial hypertrophy the ventricular myocardium starts to synthesise and release increasing amounts of BNP [5]. The left ventricular mass correlates with plasma BNP levels. This is why BNP determination has good sensitivity, but low specificity in detecting LV systolic dysfunction [17]. The association of high BNP levels to large initial damage and to the myocardial hypertrophy might explain why plasma BNP levels after MI seem to have independent prognostic value beyond the LV systolic function [11].

Several studies have demonstrated that pericardial fluid reflects the composition of cardiac interstitial fluid in normal and diseased hearts in humans [19]. Pericardial fluid is an ultrafiltrate of plasma through the myocardium. During the ultrafiltration, the fluid is enriched in molecules produced by the cardiac muscle. Diffusion of molecules up to 40 kDA, including the natriuretic peptides (MW 3 kDa), is possible [20]. In addition to the myocardial contribution, the secretion by pericardial mesothelial cells (PMC) may affect the composition of the pericardial fluid. For example, mesothelial cell cultures have been reported to express and release endothelin-1 and prostaglandins [21].

Analysis of pericardial fluid hormone concentrations has been used to study paracrine hormone release, produced by normal and diseased hearts [22]. In humans, the elevation of pericardial fluid basic fibroblast growth factor is greater in patients with ischaemic heart disease than in patients with non-ischaemic heart disease [19]. The concentration of ET-1 is higher in pericardial fluid when compared to the plasma [23]. High pericardial fluid catecholamine concentrations have been detected in spontaneously hypertensive rats [24]. Prostaglandins in the pericardial fluid have been shown to modulate neural regulation and cardiac electrophysiological properties [25].

In the present study we used pericardial fluid analyses to study paracrine ANP and BNP release from the heart. Elevated BNP but not ANP levels were detected in the pericardial fluid of patients with previous MI. The reason for this might be that plasma natriuretic peptides are derived both from heart atria and ventricles [5], whereas the pericardial fluid concentrations reflect primarily the ventricular hormone release. The production of ANP takes place mainly in the atria, whereas BNP is produced both in the atria and ventricles. Pericardial fluid analysis is therefore more sensitive in detecting increased ventricular natriuretic peptide synthesis and release.

Supporting the higher sensitivity, pericardial fluid BNP levels were increased in the patients with earlier inferior/posterior MI, whereas the plasma levels of BNP were the same as in the controls. Extremely high pericardial fluid BNP levels were detected in the patients with the history of anterior MI, when compared to the group with no MI. In linear correlation analysis no association was observed between pericardial fluid BNP levels and LV systolic function. This is in line with the earlier observation that plasma BNP levels associate with the LV mass, but have relatively weak specificity in detecting impaired LV systolic function [17].

We conclude that a previous anterior myocardial infarction is associated with increased cardiac BNP production even if the LV systolic function is normal. High pericardial fluid BNP concentrations in the postinfarction patients suggest augmentation of the BNP synthesis and release in ventricular myocardium independent from the LVEF.


   Acknowledgements
 
We thank the Finnish Cultural Foundation and the Finnish Foundation for Cardiovascular Research for the financial support.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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